Dual Inhibition of ID1 and ID3: A Promising Therapeutic Strategy for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease characterized by excessive scarring (fibrosis) of lung tissue. As fibrosis advances, lung function declines, making breathing increasingly difficult and significantly reducing quality of life. Although currently approved therapies can slow disease progression, they cannot stop or reverse established fibrosis. Identifying new therapeutic targets that directly interrupt the cellular mechanisms driving pulmonary fibrosis remains a major focus of respiratory research.

A recent study by Samar A Antar et al (2026) identifies ID1 and ID3 as promising therapeutic targets for pulmonary fibrosis. The researchers demonstrated that these proteins are significantly upregulated in both patients with idiopathic pulmonary fibrosis and multiple preclinical models of lung fibrosis, particularly within activated fibroblasts. Their findings suggest that simultaneous inhibition of ID1 and ID3 may offer a novel strategy for reducing fibrosis and preserving lung function.

Why Dual Inhibition of ID1 and ID3 Matters in Pulmonary Fibrosis

While previous work examined these proteins individually, this study highlights an important insight: ID1 and ID3 compensate for each other. Targeting just one is not enough, both must be inhibited simultaneously to see meaningful effects.

Using genetic and pharmacological approaches, the researchers demonstrated that dual inhibition of ID1/ID3:

Reduces fibroblast proliferation and migration
Prevents differentiation into fibrosis-driving myofibroblasts
Improves lung function in preclinical models using the flexiVent

Notably, treated mice showed improved flexiVent lung compliance and reduced collagen deposition – key indicators of functional recovery.

Improved Lung Function Measured Using the flexiVent System

One of the study’s most important findings was the improvement in lung mechanics following treatment. Using the flexiVent system to perform detailed pulmonary function testing, researchers observed significantly improved lung compliance in treated mice compared to untreated fibrotic controls.

Improved lung compliance, together with reduced collagen deposition, indicates that dual inhibition not only limits structural remodeling but also restores functional respiratory performance. These results highlight the value of comprehensive lung function assessment when evaluating emerging therapies for pulmonary fibrosis.

How ID1 and ID3 Drive Fibrosis

The study also provides new insight into the molecular mechanisms underlying pulmonary fibrosis.

ID1 and ID3 promote fibroblast proliferation by regulating the cell cycle, increasing expression of genes such as cyclins and CDK1 that drive cell division. When these proteins are inhibited, fibroblast expansion slows considerably.

At the same time, ID1 and ID3 activate the MEK/ERK signaling pathway, an important regulator of fibroblast differentiation. Activation of this pathway promotes the transformation of fibroblasts into collagen-producing myofibroblasts—the primary cells responsible for excessive scar tissue formation during pulmonary fibrosis.

By simultaneously suppressing cell cycle progression and MEK/ERK signaling, dual inhibition interrupts two of the fundamental biological processes responsible for fibrosis progression.

Implications for Future Pulmonary Fibrosis Therapies

This study identifies ID1 and ID3 as central regulators of fibroblast activation and highlights their potential as therapeutic targets for idiopathic pulmonary fibrosis. By blocking multiple profibrotic pathways simultaneously, dual inhibition offers a multifaceted approach that may slow—or potentially reverse—the progression of lung fibrosis.

While additional studies are needed before clinical translation, future research will likely focus on optimizing lung-targeted drug delivery, including gene therapy approaches, while minimizing off-target effects. If successfully translated to patients, therapies targeting ID1 and ID3 could represent an important advance in the treatment of pulmonary fibrosis.

This work positions ID1 and ID3 as central regulators of fibroblast activation and interesting targets for intervention. By simultaneously disrupting cell cycle progression and profibrotic signaling, dual inhibition offers a multifaceted approach to slowing or potentially reversing lung fibrosis. As research continues, strategies that refine delivery (such as lung-targeted gene therapy) and minimize off-target effects will be key to translating these findings into clinical success.

Reference

Antar, S.A., et al. Theranostics (2026). Simultaneous inhibition of ID1 and ID3 mitigates fibroblast activation via cell cycle and MEK/ERK pathways in pulmonary fibrosis. 16(11):6081-6098. doi:10.7150/thno.127118

May, 2026